Rapid progression often seen in nondiagnostic conditions

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Evolving definitions of multiple myeloma could lead to a substantial increase in the number of patients requiring evaluation and treatment.

Note that the focus on traditional risk factors has provided little help in the search for ways to identify high-risk patients who do not meet generally accepted diagnostic criteria for myeloma, and some alternate strategies have yielded encouraging results.

HOUSTON -- Evolving definitions of multiple myeloma could lead to a substantial increase in the number of patients requiring evaluation and treatment, studies of monoclonal gammopathies suggested.

The fundamental approach to the disease process has changed considerably as a result of new data high-risk conditions and disease characteristics, Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minn., said here during the Society of Hematologic Oncology meeting.

A review of 45,366 patients seen at Mayo Clinic from 1960 to 2011 showed that multiple myeloma accounted for 18% of all the patients with monoclonal gammopathies. Monoclonal gammopathy of uncertain significance (MGUS) accounted for 57% of the total.

Diagnosis of a monoclonal gammopathy rests on two events: demonstration of clonal plasma cells and demonstration of monoclonal protein in serum or urine of most patients. The primary methods for detecting these events are serum or urine protein electrophoresis or immunofixation and serum free light chain assay.

"Monoclonal plasma cells disorders represent a dynamic spectrum of activity," said Kumar. "The disease process begins with increasing levels of monoclonal protein, followed by an increasing percentage of monoclonal cells in the bone marrow. Finally, the disease progresses to development of end-organ damage."

Moving forward, the challenge will be to identify patients who do not meet current diagnostic criteria but nonetheless have a high-risk of progressive disease, Kumar said.

With respect to progression to multiple myeloma, MGUS and smoldering myeloma have very different clinical courses. MGUS has a slow but stable progression rate of about 1% per year from diagnosis. In contrast, smoldering myeloma has a rapidly progressive clinical course, such that more than half of patients meet diagnostic criteria for multiple myeloma within 5 years, two-thirds by 10 years, and 75% by 15 years.

Studies of the microvenvironment have shown a clear evolution of the clonal population. The evolutionary process begins with clonal plasma cells and absence of malignant clones (MGUS), followed over time by the appearance of clonal malignant cells (smoldering myeloma), and then a progressive increase in the malignant clones until reaching a point of predomination and eventually absence of nonmalignant clonal plasma cells (symptomatic myeloma).

Improved recognition and understanding of the evolutionary nature of progression has led to inevitable questions about the ability to intervene earlier and alter the process, Sharma said. Considerable interest has focused on preventing or reversing hypercalcemia of bone disease, which is a major driver of end-organ damage. Patients who develop renal failure secondary to hypercalcemia of bone disease may recover some kidney function, but the onset of renal failure still portends a poorer prognosis.

The focus on traditional risk factors has provided little help in the search for ways to identify high-risk patients who do not meet generally accepted diagnostic criteria for myeloma. Some alternate strategies have yielded encouraging results, such as monitoring patients with serum free-light-chain assay.

Mayo Clinic investigators studied patients with "oligosecretory myeloma," characterized by serum or urine monoclonal protein levels below the accepted diagnostic threshold. Standard electrophoresis assays cannot detect changes of 25% to 50% in response to therapy. However, serum free-light-chain assay can be used to monitor progression in such patients.

The retrospective analysis suggested that 10% of patients with newly diagnosed myeloma have preceding oligosecretory myeloma and that the condition significantly increases the likelihood of disease progression. Further analysis showed that 3% of the patients had bone marrow plasma cell concentrations of 60% or greater, and 95% of those patients subsequently progressed to multiple myeloma within 2 years (median time to progression of 7 months), Sharma said.

Another small study of patients with bone marrow infiltration of at least 60% showed that all of the patients progressed to symptomatic myeloma after a median follow-up of 15 months.

Mayo investigators have evaluated the free-light-chain ratio as a means of identifying patients with smoldering myeloma at high-risk of progression to symptomatic myeloma. Comparing serum involved/uninvolved cells, they found that 98% of patients with a serum free-light-chain ratio ≥100 progressed to symptomatic myeloma, and the median time to progression was 15 months compared with 55 months for patients with a ratio <100.

The predictive value of these alternative markers require validation, Sharma said. However, an 80% risk of progression at 2 years demonstrated in some studies "is the comfort level we want with these markers, so we can tell a patient, 'Yes, there is a really high risk of progressive disease. Let us not wait until something bad happens. Let us start treating right away.'"

Kumar disclosed no relevant relationships with industry.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner